Certain neurotransmitters act by binding to neuronal cell-surface receptors, changing intracellular levels of second messengers and the activities of their downstream effectors, and consequently altering the intrinsic properties of the neuron. This phenomenon, which is referred to as neuromodulation, is an important regulator of hippocampal pyramidal neuron function that is likely to have profound behavioral consequences. This proposal deals with investigating the molecular basis for neurotransmitter-induced neuromodulation in the hippocampus. One potentially rich site for mediating hippocampal neuromodulation is alteration of the biophysical and biochemical properties of potassium channels, as potassium channels play a major role in determining the electrical properties of hippocampal pyramidal neurons. One specific A- type potassium channel, Kv4.2, is located in the dendrites and cell bodies of pyramidal neurons in area CA1. This fact, coupled with the activation and inactivation properties of the channel, make this subtype of potassium channel ideally suited as a potential target for affecting short-term and long-term changes in the functional properties of pyramidal neurons. We are testing the hypothesis that one component of neurotransmitter-induced neuromodulation is mediated via phosphorylation of Kv4.2 We will do this by determining sites of phosphorylation of Kv4.2, directly determining if neurotransmitter application to hippocampal neurons leads to identified phosphorylation events, and dissecting the signal transduction cascades linking neurotransmitter receptors to Kv4.2 Interestingly, as part of our studies we will test the idea that the MAP kinase cascade is recruited by various neurotransmitters for modulation of Kv4.2 in the hippocampus. These studies, coupled with those described in the accompanying two proposals, should allow for the first time the definition of specific molecular events, of known physiologic consequence, as components of potassium channel-based neuromodulation in the hippocampus.